What Is Treatment-Resistant Depression?
Treatment-resistant depression (TRD) is defined as major depressive disorder that has not responded to at least two adequate antidepressant trials — meaning the correct dose, taken for a sufficient duration (typically 6–8 weeks each).
It is more common than most people realize. Approximately 30% of people with major depression do not achieve remission with standard antidepressants. These patients often spend years cycling through medications — each with side effects, partial responses, and eventual failure — before being told there are no other options. That conclusion is incorrect.
Prevalence in Israel
Depression is among the most prevalent mental health conditions in Israel, affecting an estimated 8–12% of the population across their lifetime. A substantial subset will not respond adequately to standard psychiatric treatment. Yet awareness of validated alternatives — including ketamine therapy — remains limited in the Israeli medical landscape.
Why Antidepressants Sometimes Fail
The dominant model of depression as 'low serotonin' is an oversimplification. Depression involves complex disruptions across multiple neurotransmitter systems, stress hormones, inflammatory pathways, and neural circuit function. SSRIs and SNRIs address only the serotonin and norepinephrine components.
Additional factors include genetic variability in drug metabolism (pharmacogenomics), inflammatory subtypes of depression that are minimally responsive to serotonergic agents, and neural atrophy — structural changes in the hippocampus and prefrontal cortex associated with chronic depression that antidepressants may not adequately reverse.
The Neuroscience of Neuroplasticity
Neuroplasticity refers to the brain's capacity to reorganize itself — forming new synaptic connections and repairing atrophied neural circuits. Chronic depression is associated with reduced neuroplasticity. Effective treatment must restore it.
Ketamine acts on NMDA receptors in the glutamate system — the brain's primary excitatory neurotransmitter pathway, distinct from the serotonin system targeted by SSRIs. NMDA blockade by ketamine triggers release of BDNF (brain-derived neurotrophic factor) and activates the mTOR pathway, promoting rapid synaptogenesis — new synaptic connections — within hours of administration.
This neuroplasticity window, most potent in the hours to days following a ketamine session, is precisely when psychotherapeutic integration can produce durable behavioral and emotional change.
The Ketamine Evidence Base
Ketamine's antidepressant properties have been studied since the early 2000s, with a robust and growing literature. Key findings include response rates of 60–75% in treatment-resistant populations, significant antidepressant effects within 24 hours (unique among all psychiatric medications), rapid and specific reduction in suicidal ideation, and evidence of benefit in PTSD and complex trauma.
The FDA's 2019 approval of esketamine (Spravato) — a ketamine derivative — for TRD marked a major institutional validation of the ketamine mechanism. Racemic ketamine, used in KAP, has been used in psychiatric practice for decades with a well-established evidence base.
If you have not found relief from antidepressants, a free screening call with Dr. Rosenbach is the first step to exploring whether KAP may be appropriate for you.
